Project Summary The emergence and rapid spread of carbapenem-resistant Enterobacteriaceae (CRE) represents a major public health threat. Infections due to CRE are associated with significant morbidity and mortality, due in part to limited antibiotic treatment options. The polymyxins, including colistin, are important last-line therapeutic agents for CRE infections, including as part of combination antibiotic regimens that may reduce mortality. However, cases of colistin-resistant CRE (colR-CRE) have been recently reported worldwide, and represent a major therapeutic challenge, as there are no well-studied treatment options available. Post-acute care settings, and long-term acute care hospitals (LTACHs) in particular, are increasingly important sites of clinical care in the United States. LTACHs, which are defined by the Centers for Medicare and Medicaid Services (CMS) as acute care hospitals with an average length of stay of ?25 days, are characterized by a chronically, critically-ill population with high rates of antibiotic exposure, indwelling device use, and mechanical ventilation. These characteristics significantly increase the risk of colonization and infection with colR-CRE in this population. Rates of colR-CRE are also amplified in LTACHs due to the convergence of complex, high-risk transfers from multiple acute care hospitals to a single facility. For all of these reasons, LTACHs are likely to be critical in the emergence and transmission of colR-CRE. However, there is a significant lack of data on the clinical and molecular epidemiology of colR-CRE specifically in the LTACH setting. This proposal adopts an interdisciplinary approach, and will link the clinical and molecular epidemiology of colR-CRE to substantially improve the understanding of this highly drug-resistant pathogen in the LTACH setting. The Specific Aims of this proposal include the following: Aim 1: To identify risk factors for colonization or infection with colR-CRE in LTACH patients; Aim 2: To evaluate the impact of colR-CRE colonization or infection on mortality in the LTACH setting; Aim 3: To use whole-genome sequencing to prospectively evaluate colR-CRE isolates from a regional network of LTACHs with a high baseline prevalence of CRE. The completion of the proposed research aims will provide critical insights into the clinical and molecular epidemiology of colistin resistance in CRE in a healthcare setting of increasing importance. Elucidation of the epidemiology of colR-CRE will significantly inform the development of effective infection prevention and antibiotic stewardship strategies to limit the emergence and transmission of these organisms. In addition, a broader understanding of the epidemiology of colR-CRE in LTACHs is critical for reducing rates of colR-CRE across highly connected short-term and long- term acute care settings, including understanding the role of LTACHs as sentinel facilities for the emergence of colR-CRE.